When delivered at a sufficient dose and dose rate to a neoplastic mass, radiation can kill tumor cells. Because cancer frequently presents as a disseminated disease, it is imperative to deliver ...cytotoxic radiation not only to the primary tumor but also to distant metastases, while reducing exposure of healthy organs as much as possible. Monoclonal antibodies and their fragments, labeled with therapeutic radionuclides, have been used for many years in the development of anticancer strategies, with the aim of concentrating radioactivity at the tumor site and sparing normal tissues. This review surveys important milestones in the development and clinical implementation of radioimmunotherapy and critically examines new trends for the antibody-mediated targeted delivery of radionuclides to sites of cancer.
In analogy to ubiquitin in eukaryotes, the bacterial protein Pup is attached to lysine residues of substrate proteins, thereby targeting them for proteasomal degradation. It has been proposed that, ...before its attachment, Pup is modified by deamidation of its C-terminal glutamine to glutamate. Here we have identified Dop (locus tag Rv2112) as the specific deamidase of Pup in Mycobacterium tuberculosis. Deamidation requires ATP as a cofactor but not its hydrolysis. Furthermore, we provide experimental evidence that PafA (locus tag Rv2097) ligates deamidated Pup to the proteasomal substrate proteins FabD and PanB. This formation of an isopeptide bond requires hydrolysis of ATP to ADP, suggesting that deamidated Pup is activated for conjugation via phosphorylation of its C-terminal glutamate. By combining these enzymes, we have reconstituted the complete bacterial ubiquitin-like modification pathway in vitro, consisting of deamidation and ligation steps catalyzed by Pup deamidase (Dop) and Pup ligase (PafA).
The rupture of the anterior cruciate ligament (ACL) is one of the most common injuries of the knee. Women have a higher injury rate for ACL ruptures than men. Various indicators for this sex-specific ...difference are controversially discussed.
A systematic review of the literature that compares surface electromyography (EMG) values of adult female and male subjects to find out if there is a difference in neuromuscular activation of the knee stabilizing muscles.
This systematic review has been guided and informed by the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Studies which examined sex-specific differences with surface EMG measurements (integral, root mean squares, mean values, analysis of time and amplitude) of the knee stabilizing muscles were retrieved via searches from the databases PubMed, CINAHL, Embase, CENTRAL and SPORTDiscus. The risk of bias of included studies was assessed with the National Heart, Lung and Blood Institute (NHLBI) study quality assessment tool. A synthesis of results was performed for relevant outcomes.
Fifteen studies with 462 healthy participants, 233 women (mean age 21.9 (± 2.29) years) and 299 men (mean age 22.6 (± 2.43) years), were included in the systematic review. The methodological quality of the studies was mostly rated "fair" (40%). A significantly higher activity of the muscles vastus lateralis and vastus medialis was found in females, in three studies. Two studies found significantly lower neuromuscular activity in the muscles biceps femoris and semitendinosus in females. All other included studies found no significant differences or reported even contradicting results.
The controversial findings do not allow for a concluding answer to the question of a sex-specific neuromuscular activation. Further research with higher statistical power and a more homogeneous methodical procedure (tasks and data normalisation) of the included studies may provide insight into possibly existing sex-specific differences in neuromuscular activation. This systematic review could help to improve the methodical design of future studies to get a more valid conclusion of the issue.
CRD42020189504.
This study investigated age‐dependent improvements of monitoring and control in 7/8‐ and 9/10‐year‐old children. We addressed prospective (judgments of learning and restudy selections) and ...retrospective metacognitive skills (confidence judgments and withdrawal of answers). Children (N = 305) completed a paired‐associate learning task twice, with a 1‐year delay. Results revealed improvements in retrospective, but not in prospective monitoring and control. Furthermore, control remained suboptimal, seemingly a consequence of overoptimistic monitoring. Both age groups showed stronger monitoring‐based control at the second compared to the first assessment. The comparison with a cross‐sectional sample (N = 144) revealed that improvements in retrospective monitoring can be mainly attributed to naturally occurring development, whereas retrospective control seemed to improve due to increased task familiarity.
Two independent data sets assessing children's metacognitive monitoring abilities were used to explore the psychometric properties of classical and often-used monitoring measures in primary school ...age. Theoretically, monitoring is an overarching skill that helps individuals evaluate task mastery, strategy use, and correctness of performance. Monitoring skills are increasingly targeted when addressing individual differences in scholastic achievement and intervention approaches to foster students' self-regulated learning early on. In such contexts, knowledge about central psychometric properties is essential. Results of both studies revealed high internal consistency of prospective and retrospective monitoring judgments. When equivalent item sets (in terms of item difficulty) were considered (Study 1), split-half reliabilities were also satisfying. However, analyses revealed that the monitoring judgments' reliability depends on the reliability of the first-order task (recognition memory test). Retesting children of Study 2 after six months revealed considerable fluctuations in the monitoring measures. Among the included monitoring measures, reliabilities of within-person correlations (Gammas) between performance and confidence and recognition response times and confidence were poorest. Results are discussed in the context of the underlying theoretical construct and implications for research and practice.
The aim of this study was to describe the characteristics of patients with uveitis associated with an immunologic or idiopathic disease that requires immunosuppressive treatment and the response to ...such treatments in real clinical practice.
An observational, descriptive, longitudinal, and retrospective study of a cohort of patients diagnosed with noninfectious uveitis was performed. To assess the response to treatment, we evaluated the change in visual acuity, vitritis, and the presence of macular edema.
We included 356 patients. Overall, 12% required treatment with systemic corticosteroids, and 66 patients (18.5%) required immunosuppressive/biological treatment, with methotrexate being the most used (55%). Immunosuppressive drugs were used in 59 cases (in 56 patients, as the first choice of treatment and for 3 patients as the second choice after treatment with biologics). Treatment with biologics was the first choice in 10 patients out of 66 (15%), and 34 (48%) required them at some time during the disease, with adalimumab being the most commonly used. Thirty-five patients (53%) needed to switch drugs due to a lack of response to the first one. There were no differences between different drugs in the resolution of vitritis and improvement in vision.
The use of systemic corticosteroids and immunosuppressive/biologics was necessary for a high number of patients with noninfectious uveitis. In our series, tocilizumab was significantly more effective in the resolution of macular edema.
Background. The risk of herpes zoster reactivation is increased in immunocompromised patients, especially in those with immune-mediated inflammatory diseases (IMIDs) on Janus kinase inhibitor (JAKi) ...treatment. The recombinant subunit herpes zoster vaccine (RZV) is a non-live vaccine, recently approved for this subgroup of patients, which shows high rates of vaccine effectiveness, with few adverse effects reported in clinical trials. Purpose. The aim of this real-world study was to determine the immunogenicity and safety of RZV in IMID patients on JAKi treatment. Methods. The increase in the concentration of anti-gE antibody for varicella zoster virus post-vaccination, compared to the pre-vaccination concentration, was analyzed to test the humoral immune response. Adverse effects after the first and second vaccine doses were registered. Results. In total, 49 patients were analyzed, and a fourfold increase in antibody concentration was achieved in almost 40% of subjects, with only one serious local adverse effect. Discussion. The resulting immunogenicity was lower than that observed in clinical trials, probably due to the presence of immune disease and immunosuppressive treatment, and to the fact that this was a real-world study. No differences in response according to age, previous virus zoster reactivation, or concomitant treatments were found. Conclusions. RZV was well tolerated and reached the immune response objective in 40% of patients. These results reinforce the importance of including RZV vaccination for immunosuppressed patients. Real-world studies regarding vaccine effectiveness are still needed in order to gain a full understanding of the response to RZV in this group of patients.
Low-dose radon hyperthermia balneo treatment (LDRnHBT) is applied as a traditional measure in the non-pharmacological treatment of rheumatic diseases in Europe. During the last decades, the main ...approach of LDRnHBT was focused on the treatment of musculoskeletal disorders, but scientific evidence for the biological background of LDRnHBT is weak. Recently, evidence emerged that LDRnHBT influences bone metabolism. We investigated, whether combined LDRnHBT and exercise treatment has an impact on bone metabolism and quality of life in a study population in an age group at risk for developing osteoporosis. This randomized, double-blind, placebo-controlled trial comprised guided hiking tours and hyperthermia treatment in either radon thermal water (LDRnHBT) or radon-free thermal water (PlaceboHBT). Markers of bone metabolism, quality of life and somatic complaints were evaluated. Statistics was performed by linear regression and a linear mixed model analysis. Significant changes over time were observed for most analytes investigated as well as an improvement in self-assessed health in both groups. No significant impact from the LDRnHBT could be observed. After 6 months, the LDRnHBT group showed a slightly stronger reduction of the osteoclast stimulating protein receptor activator of nuclear kB-ligand compared to the PlaceboHBT group, indicating a possible trend. A combined hyperthermia balneo and exercise treatment has significant immediate and long-term effects on regulators of bone metabolism as well as somatic complaints. LDRnHBT and placeboHBT yielded statistically equal outcomes.
The fungus
, the cause of invasive aspergillosis (IA), is a serious risk to transplant patients and those with respiratory diseases. Host immune suppression is considered the most important factor ...for the development of IA. Less is known about the importance of fungal virulence in the development of IA including the significance of variation between isolates. In this study, isolates of
from cases diagnosed as having proven IA or colonisation (no evidence of IA) were compared in assays to measure isolate virulence. These assays included the measurement of radial growth and protease production on agar, sensitivity to UV light and oxidative stressors, and virulence in
(mealworm) larvae. These assays did not reveal obvious differences in virulence between the two groups of isolates; this provided the impetus to conduct genomic analysis. Whole genome sequencing and analysis did not allow grouping into coloniser or IA isolates. However, focused analysis of single nucleotide polymorphisms revealed variation in three putative genes: AFUA_5G09420 (
), AFUA_4G00330, and AFUA_4G00350. These are known to be responsive to azole exposure, and
deletion leads to azole hypersensitivity in other fungi.
virulence is challenging, but the findings of this study indicate that further research into the response to oxidative stress and azole exposure are required to understand the development of IA.
Patients with different autoimmune inflammatory diseases (AIID) on biological therapy are at risk of pneumococcal disease. Adults with inflammatory arthropathies, connective tissue diseases, ...psoriasis, or inflammatory bowel disease on biological therapy such as anti-TNFα, rituximab, tocilizumab, abatacept, or anakinra were included in this study. Patients completed a protocol combining the pneumococcal vaccines PCV13 and PPV23. Immune response against pneumococcal serotypes 1, 3, 7F, 14, 19A, and 19F were assessed evaluating functional antibodies by an opsonophagocytosis killing assay (OPKA). In this study, 182 patients with AIID completed the sequential vaccination protocol. Patients on etanercept tended to achieve OPKA titers against a larger number of serotypes than the rest of patients on other biological therapies, while adalimumab was associated to a lower number of serotypes with OPKA titers. Rituximab was not associated with a worse response when compared with the rest of biological agents. Not glucocorticoids, nor synthetic disease-modifying antirheumatic drugs, interfered with the immune response. OPKA titers against serotype 3 which is one of the most prevalent, was obtained in 44% of patients, increasing up to 58% in those on etanercept. Hence, almost 50% of patients on biological therapy achieved functional antibodies after the administration of a complete pneumococcal vaccination protocol.
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